Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

Afdhal, Nezam H.; Zeuzem, Stefan; Kwo, Paul Y.; Chojkier, Mario; Gitlin, Norman; Puoti, Massimo; Romero–Gómez, Manuel; Zarski, Jean Pierre; Agarwal, Kosh; Buggisch, Peter; Foster, Graham R.; Bräu, Norbert; Buti, Marı́a; Jacobson, Ira M.; Subramanian, G. Mani; Ding, Xiao; Mo, Hongmei; Yang, Jenny C.; Pang, Phillip S.; Symonds, William T.; McHutchison, John G.; Muir, Andrew J.; Mangia, Alessandra; Marcellin, Patrick

doi:10.1056/nejmoa1402454

Cited by 1,582 publications

(1,544 citation statements)

References 17 publications

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“…Phase III trials that evaluated the effect of ledipasvir (LDV) and sofosbuvir (SOF) in 1900 treatment-naïve and treatment-experienced patients with genotype 1 showed two cases of virological breakthrough on treatment. Both patients were suspected of nonadherence 17,18. A further study of LDV/SOF with or without ribavirin (RBV) in patients with genotype 1 and cirrhosis, who were nonresponsive to previous protease inhibitor therapy, recorded medication adherence as either <80% or >80%.…”

Section: Medication Adherence In a Chronic Disease Settingmentioning

confidence: 99%

The Australasian Hepatology Association consensus guidelines for the provision of adherence support to patients with hepatitis C on direct acting antivirals

Richmond¹,

Sheppard‐Law²,

Mason³

et al. 2016

PPA

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BackgroundHepatitis C is a blood-borne virus primarily spread through sharing of drug-injecting equipment. Approximately 150 million people worldwide and 230,000 Australians are living with chronic hepatitis C infection. In March 2016, the Australian government began subsidizing direct acting antivirals (DAAs) for the treatment of hepatitis C, which are highly effective (95% cure rate) and have few side effects. However, there is limited evidence to inform the provision of adherence support to people with hepatitis C on DAAs including the level of medication adherence required to achieve a cure.MethodologyIn February 2016, a steering committee comprising four authors convened an expert panel consisting of six hepatology nurses, a hepatologist, a pharmacist, a consumer with hepatitis C and treatment experience, and a consumer advocate. The expert panel focused on the following criteria: barriers and enablers to DAA adherence; assessment and monitoring of DAA adherence; components of a patient-centered approach to DAA adherence; patients that may require additional adherence support; and interventions to support DAA adherence. The resultant guidelines underwent three rounds of consultation with the expert panel, Australasian Hepatology Association (AHA) members (n=12), and key stakeholders (n=7) in June 2016. Feedback was considered by the steering committee and incorporated if consensus was achieved.ResultsTwenty-four guidelines emerged from the evidence synthesis and expert panel discussion. The guidelines focus on the pretreatment assessment and education, assessment of treatment readiness, and monitoring of medication adherence. The guidelines are embedded in a patient-centered approach which highlights that all patients are at risk of nonadherence. The guidelines recommend implementing interventions focused on identifying patients’ memory triggers and hooks; use of nonconfrontational and nonjudgmental language by health professionals; and objectively monitoring adherence.ConclusionThese are the first guidelines to support patients and health professionals in the delivery of clinical care by identifying practical adherence support interventions for patients taking DAAs.

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Section: Medication Adherence In a Chronic Disease Settingmentioning

confidence: 99%

The Australasian Hepatology Association consensus guidelines for the provision of adherence support to patients with hepatitis C on direct acting antivirals

Richmond¹,

Sheppard‐Law²,

Mason³

et al. 2016

PPA

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“…High response rates are observed in patients with compensated cirrhosis in clinical trials [1][2][3][4] and in real-life observational studies [5]. Even in patients with decompensated cirrhosis, for whom pegylated interferon is contraindicated and who otherwise have a poor prognosis, HCV can now be cured safely and effectively [6].…”

Section: Introductionmentioning

confidence: 99%

Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis

Foster

Irving

Cheung

et al. 2016

Journal of Hepatology

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441

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…The pangenotypic NS5B HCV inhibitor sofosbuvir (SOF) has demonstrated high efficacy in patients infected with HCV in combination with ledipasvir (LDV) for genotype (GT) 1, 2, 4, 5, and 62, 3, 4, 5, 6, 7 and in combination with ribavirin (RBV) with or without pegylated interferon for GT3 HCV 8, 9. SOF exhibits a high barrier to resistance in vivo.…”

mentioning

confidence: 99%

The emergence of NS5B resistance associated substitution S282T after sofosbuvir‐based treatment

Gane

Métivier

Nahass³

et al. 2017

Hepatology Communications

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S282T in NS5B is the primary amino acid substitution associated with resistance to sofosbuvir (SOF) but has rarely been detected in patients treated with a SOF‐based regimen. Here, the emergence and fitness of the S282T substitution in virologic failure patients administered SOF‐based regimens across the SOF and ledipasvir (LDV)/SOF phase 2 and 3 programs was evaluated. Plasma samples collected at baseline and at virologic failure were amplified and deep sequenced (1% cutoff). To date, over 12,000 patients have been treated in SOF or LDV/SOF phase 2 and 3 studies. Of these, deep sequencing was available at baseline in 8598 patients (62.4% genotype [GT] 1, 10.7% GT2, 20.9% GT3, and 6.0% GT4‐6) and at virologic failure in 901 patients. In the 8598 patients, no S282T substitution was detected at baseline; at virologic failure, 10 of the 901 (1%) patients had S282T detected. The SOF‐based regimen associated with treatment‐emergent S282T was SOF monotherapy in two patients, retreatment with LDV/SOF in prior LDV/SOF failures in three patients, LDV/SOF for 8 weeks in 1 GT1 patient, LDV/SOF for 12 weeks in 1 patient each with GT3, GT4, and GT5, and LDV/SOF + ribavirin for 12 weeks in 1 GT6 patient. Nine of 10 patients with emergent S282T received an SOF‐based retreatment regimen, eight of whom achieved sustained virologic response 12 weeks after treatment and one of whom failed retreatment. Conclusion: The emergence of S282T substitution was rare in patients who fail SOF‐based regimens. Successful retreatment of prior SOF failure patients is possible in the presence of S282T substitution with SOF in combination with various direct‐acting antiviral agents. (Hepatology Communications 2017;1:538–549)

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Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

Cited by 1,582 publications

References 17 publications

The Australasian Hepatology Association consensus guidelines for the provision of adherence support to patients with hepatitis C on direct acting antivirals

The Australasian Hepatology Association consensus guidelines for the provision of adherence support to patients with hepatitis C on direct acting antivirals

Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis

The emergence of NS5B resistance associated substitution S282T after sofosbuvir‐based treatment

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